Excessive adiposity is a risk factor for many chronic diseases, including type 2 diabetes mellitus (T2DM), cardiovascular disease, and cancer (Wang, McPherson et al. 2011). Studies have shown that even a modest reduction in weight has a positive impact on cardiovascular risk factors (Blackburn 1995; Pi-Sunyer 1996) and is associated with a reduced risk for both developing T2DM and diabetes-associated complications (Bosello, Armellini et al. 1997).
Lifestyle interventions aimed at reducing calories and increasing physical activity through behavioral changes are currently recommended as the first-line approach for weight management. However, these strategies alone are less successful when compared to pharmacological interventions for maintained weight loss (6 to 12 months) (Gray, Cooper et al. 2012). Unfortunately, most of the drugs approved for the treatment of obesity have been withdrawn from use due to their side effects (Gray, Cooper et al. 2012). Recently, targeting of gut hormones for the treatment of obesity has garnered interest (Neary and Batterham 2009). Indeed, infusion of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) are able to reduce appetite by acting on feeding regions of the brain in humans (De Silva, Salem et al. 2011). Another promising candidate is the stomach-derived peptide hormone ghrelin. Ghrelin levels peak in circulation during energy depleted states leading to activation of the appetite stimulating neuropeptide Y (NPY) and Agouti gene-related peptide (AgRP) neurons within the arcuate nucleus of the hypothalamus (Nakazato, Murakami et al. 2001). This action occurs via ghrelin binding to the growth hormone secretagogue receptor (GHS-R1a) (Kamegai, Tamura et al. 2000). In addition to appetite, ghrelin promotes the differentiation of adipocytes and the preference for storage of calories in adipose tissue (Tschop, Smiley et al. 2000; Rodriguez, Gomez-Ambrosi et al. 2009).
The ghrelin peptide is derived from proghrelin, which is a precursor peptide proteolytically cleaved to produce acylated ghrelin (AG) (Zhu, Cao et al. 2006), unacylated ghrelin (UAG) (Zhu, Cao et al. 2006) and obestatin (Zhang, Ren et al. 2005). However, in vitro studies have shown that both UAG (Kojima, Hosoda et al. 1999) and obestatin (Zhang, Ren et al. 2005) are unable to bind to GHS-R1a. The GHS-R1a is a G-protein-coupled receptor (Howard, Feighner et al. 1996), and is activated through the binding of its only known endogenous ligand, AG (Kojima, Hosoda et al. 1999). A recent study suggested that AG binds to GHS-R1a in the second extracellular loop (EC2), which forms a hydrophobic pocket, allowing the lipophylic acylated side chain of ghrelin to be stabilized during the binding (Pedretti, Villa et al. 2006).